1. Technical Field
The invention relates to diagnosis of sudden cardiac death or potential for sudden cardiac death in patients who have mutations in ion channels proteins involved in electrophysiology of the heart.
2. Background of Related Art
Sudden cardiac death takes the lives of over 300,000 Americans annually. Malignant ventricular arrhythmias occurring in individuals with structurally normal hearts account for a subgroup of these sudden deaths. This form of cardiac disease accounts for approximately 20% of sudden cardiac death cases. Recent years have witnessed major strides in the understanding of sudden cardiac death in individuals with structurally normal heart. Idiopathic, sudden cardiac death syndromes for which there was previously no explanation are gradually coming into focus as forms of inherited ion channelopathies.
The QT interval is the surrogate electrocardiographic index of ventricular repolarization and its duration under normal conditions is mainly determined by expression, properties, and balance of the repolarising inward sodium and calcium and outward potassium and chloride currents. Ion channels proteins are responsible for the currents that comprise the cardiac action potential and alterations in ion channel function are known to be associated with a wide spectrum of phenotypes. Long QT syndrome (LQT) is characterized by the appearance of a long QT interval in the electrocardiogram, and an atypical polymorphic ventricular tachycardia known as torsades de pointes, and a high risk of sudden cardiac death. Congenital LQT syndrome is an inherited condition of abnormal cardiac repolarization. Acquired LQT syndrome is similar to congential LQT syndrome but can be caused by exposure to drugs, trauma or other environmental factors. Gain of function in SCN5A, the gene that encodes for the α subunit of the cardiac sodium channel, is associated with the LQT3 form of the Long QT syndrome (See, e.g., U.S. Pat. No. 5,599,673), while a decrease in function of the same channel is associated with Brugada syndrome and familial conduction disease. Likewise, loss of function in IKs and IKr is linked to other forms of Long QT, while an increase in IKs current, caused by a mutation in the α subunit KCNQ1 (also referred to as KvLQT1), is linked to familial atrial fibrillation. The final common pathway is similar, involving alteration of ion channel activity, leading to the development of an arrhythmogenic substrate.
U.S. Pat. Nos. 6,582,913, 6,451,534, 6,432,644 and 6,277,978 are directed to screening and/or diagnosis of Long QT syndrome by analyzing the DNA sequence of the KvLQT1 or KCNE1 genes and molecular variants of these genes which cause or are involved in the pathogenesis of Long QT syndrome. U.S. Pat. Nos. 6,420,124 and 6,274,332 are directed to screening for drugs useful in treating a person having certain mutations in the KvLQT1 or KCNE1 genes. U.S. Pat. No. 6,458,542 is directed to a method for screening for susceptibility to drug induced cardiac arrhythmia by detecting a polymorphism in the KCNE1 gene. Certain mutations in the HERG (also known as KCNH2) gene have also been linked to LQT syndrome. See, e.g., U.S. Pat. No. 6,207,383.
Brugada syndrome is associated with sudden cardiac death and ventricular arrhythmia and may occur in the structurally normal heart. It is characterized by ST segment elevation in the right precordial leads (V1 to V3) and right bundle branch block. The age of onset of clinical manifestations, which can include syncope or cardiac arrest, is typically in the third or fourth decade of life. Cardiac events may occur during sleep or at rest. A loss of ion channel function in Brugada syndrome has been associated with certain mutations of the SCN5A protein.
Progressive cardiac conduction defect, also known as progressive conduction disease or Lenegre disease is another electrophysiological cardiac syndrome that is considered one of the most common. It is characterized by a progressive alteration of cardiac conduction through the atrioventricular node, His-Purkinje system with left or right bundle block, which may cause syncope or sudden death. Scott et al., Nat. Genet., (1998) 23:20-21, indicate that certain mutations in SCN5A are associated with progressive conduction disease.
Short QT syndrome (SQT) is a new clinical entity originally described in 2000. Short QT syndrome is characterized by the presence of a very short QT interval in the electrocardiogram (Bazzett-corrected QT interval (QTc) of ≦300 msec), episodes of paroxysmal atrial fibrillation, ventricular arrhythmias and possible sudden death in patients with structurally normal hearts. An autosomal dominant pattern of transmission with a high incidence of sudden death over several generations has been reported.
There is a need to determine the underlying cause of sudden cardiac death so that diagnostic procedures can be implemented to take precautions in susceptible individuals and to aid in determinations of mortality risk.